Intracellular pharmacokinetics of anthracyclines in human leukemia cells: correlation of DNA-binding with apoptotic cell death.
Anthracyclines are major components of the most therapeutical strategies in hematological oncology. These drugs are not directly cytotoxic but induce apoptosis. Due to their lipophilicity, anthracyclines are rapidly distributed in myeloid and lymphatic leukemia cells. Within 20 min after treatment, daunorubicin and idarubicin are found to intercalate into DNA. Shortly after treatment, DNA damage occurs and increases within 3 hours. Apoptosis can be monitored 12-24 hours after treatment, at this timepoint the majority of DNA strand breaks have already been repaired. A statistically highly significant linear correlation could be established between the DNA binding rate of anthracyclines and the resulting cell death. This indicates that DNA binding is a prerequisite for the induction of apoptosis. With respect to cellular resistance mechanisms, 2 different pharmacodynamic phases can be distinguished: intracellular distribution and cellular reaction. The endpoint of the "distribution phase" is marked by the DNA intercalation of the anthracyclines. Cellular resistance mechanisms which decrease the DNA binding include membrane transport mechanisms and vesicular trapping of the drugs. The "reaction phase" might be disturbed by complex antiapoptotic mechanisms. The assessment of DNA binding in malignant cells during or shortly after treatment with anthracyclines might be a useful tool to distinguish cellular resistance mechanisms.
Gieseler
F
F
University Hospital, Medizinische Poliklinik, Würzburg, Germany.
Nüssler
V
V
Brieden
T
T
Kunze
J
J
Valsamas
S
S
D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects*; D002467:Cell Nucleus / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism*; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D018922:HL-60 Cells; D006801:Humans; D015255:Idarubicin / Q000493:pharmacokinetics; D007938:Leukemia / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; C054440:idarubicinol; D015255:Idarubicin; D003630:Daunorubicin